(Circulation. 1995;91:1847-1854.)
© 1995 American Heart Association, Inc.
Articles |
Cholesterol Derivative of a New Triantennary Cluster Galactoside Lowers Serum Cholesterol Levels and Enhances Secretion of Bile Acids in the Rat
Presented in part at the 66th Scientific Sessions of the American Heart Association and in abstract form (Circulation. 1993;88:465).
From the Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, Sylvius Laboratory, University of Leiden (the Netherlands).
Correspondence to Erik A.L. Biessen, PhD, Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, Sylvius Laboratory, University of Leiden, PO Box 9503, 3200 RA Leiden, Netherlands.
Background Previous studies have demonstrated that cholesterol-derivatized galactosides exert a hypocholesterolemic effect by inducing hepatic uptake of atherogenic lipoproteins by means of galactose-recognizing receptors in the liver. However, a prolonged infusion of high concentrations of these compounds was required for this effect, possibly because of low affinity for the galactose-recognizing asialoglycoprotein receptor on the parenchymal liver cell.
Methods and Results We have designed a new series of
triantennary galactosides to optimize the affinity and specificity for
this receptor. The affinity of a triantennary galactoside for the
asialoglycoprotein receptor appeared to be dramatically enhanced by
proper spacing of the three terminal galactose groups. In rats, a
single injection of
N-[tris-O-(3,6,9-trioxaundecanyl-ß-D-galactopyranosyl)methoxymethyl]methyl-N
-[1-(6-(5-cholesten-3ß-yloxy)glycyl)adipyl]glycinamide
[TG(20Å)C], the cholesterol derivative of the most selective
galactoside, causes a dose-dependent decrease of 
45% in the serum
cholesterol concentration (P<.001). This decrease is mainly
attributed to a decrease in the level of serum HDL (P=.0066)
and, to a lesser extent, serum LDL (P=.036). In addition,
TG(20Å)C strongly enhances the bile-acid secretion in rats during the
first 2 hours after administration, which indicates that
TG(20Å)C-induced clearance of cholesterol from the bloodstream is
efficiently coupled to hepatic bile-acid secretion.
Conclusions We conclude that TG(20Å)C efficiently directs lipoproteins that contain cholesterol to the liver at a 30-fold-lower concentration than previously developed cholesterol-derivatized cluster galactosides. This newly developed approach to lower cholesterol levels may prove valuable for familial hypercholesterolemic patients or those with familial defective apolipoprotein B-100 who do not respond or who respond insufficiently, respectively, to conventional therapies.
Key Words: hypercholesterolemia • cholesterol • lipoproteins
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